2-hydroxy-N,N-dimethylbenzamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In an argon atmosphere, a mixture of 6.55 g (39.7 mmol) of 15, 10.9 g (79.3 mmol) of K2CO3, 1.0 g (5.94 mmol) of KI and 80 mL of anhydrous DMF was stirred for 10 min at room temperature. After that 7.52 g (59.5 mmol) of benzyl chloride was added in one portion. The resulting mixture was stirred for 2 hr at 70° C. and then evaporated to dryness. To the residue, 70 mL of water and 30 mL of dichloromethane were added. The organic layer was separated, and the aqueous layer was washed by 2×50 mL of dichloromethane. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. The residue was washed by 50 mL of cold ether and dried in vacuum. Yield 9.71 g (96%) of a white solid. The resulting mixture was stirred for 2 hr at 70° C. evaporated to dryness To the residue, 70 mL of water and 30 mL of dichloromethane were added The organic layer was separated the aqueous layer was washed by 2×50 mL of dichloromethane The combined organic extract was dried over Na2SO4 evaporated to dryness The residue was washed by 50 mL of cold ether dried in vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 156 g (1.13 mol) of salicylic acid and 471 g (3.96 mol) of thionyl chloride was stirred for 4 hr at 50° C.-60° C. Excess thionyl chloride was distilled off under vacuum, and the residue was additionally dried in vacuum. A solution of this product in 300 mL of dichloromethane was added dropwise with vigorous stirring to a mixture of 270 g (3.31 mol) of dimethylamine hydrochloride and 702 g (6.95 mol) of triethylamine in 1200 mL of dichloromethane for 1 hr at 0° C. The resulting mixture was slowly warmed to room temperature, stirred for 1 hr, and then filtered through glass frit. The precipitate was additionally washed with 300 mL of dichloromethane. The combined filtrate was washed by 5% hydrochloric acid, water, dried over K2CO3, and then evaporated to dryness. The residue was washed with 200 mL of diethyl ether to yield 112 g (60%) of white solid. Excess thionyl chloride was distilled off under vacuum the residue was additionally dried in vacuum A solution of this product in 300 mL of dichloromethane was added dropwise stirred for 1 hr filtered through glass frit The precipitate was additionally washed with 300 mL of dichloromethane The combined filtrate was washed by 5% hydrochloric acid, water dried over K2CO3 evaporated to dryness The residue was washed with 200 mL of diethyl ether

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a three neck flask was charged (50.0 g, 190.8 mmol) of 5-bromo-3-nitro-salicylic acid (Davos, 464 Hudson Terrace, Englewood, N.J. 07362), 200 ml of acetonitrile and 14 ml (191.9 mmol) of thionyl chloride. The resulting mixture was heated at 70° C. for 2 hours. The mixture was then cooled to 5-10° C. and a solution of dimethylamine in THF (2M, 210 ml, 2.2 eq.) was added slowly over one hour. The reaction mixture was then warmed to ambient temperature and stirred for another 3 hours. The mixture was mixed with 100 ml of water and acidified with sulfuric acid (2N, 45 ml) to a pH of 2. Additional 800 ml of water was added slowly over one hour while solids product precipitated out from the mixture. The suspension was cooled to 5° C. The solids were filtered and washed with water (200 ml). The wet crude product was recrystallized from 400 ml of hot ethanol to give 44.2 g (80%) of the compound of formula IV(a). Melting point: 181° C.-183° C. 1H NMR (400 MHz, DMSO): δ (ppm) 10.94 (s, 1H), 8.16 (d, 1H, J=2.5 Hz), 7.76 (d, 1H, J=2.5 Hz), 2.9 (br, 6H). 13C NMR (100.62 MHz, DMSO): 164.7, 147.5, 137.6, 135.9, 131.5, 127.4, 110.0, 37.6, 34.3. Anal. calcd. for C9H9BrN2O4 (289.08): C, 37.39; H, 3.14; N, 9.69. Found: C, 37.42; H, 2.90; N, 9.55. The mixture was then cooled to 5-10° C. The reaction mixture was then warmed to ambient temperature precipitated out from the mixture The suspension was cooled to 5° C The solids were filtered washed with water (200 ml) The wet crude product was recrystallized from 400 ml of hot ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The entitled compound was obtained in the same method as in Example 14 or in accordance with the method or by combining it with an ordinary method but using 4-fluoro-5-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14 and 2-hydroxybenzoic acid dimethylamide in order. The entitled compound was obtained in the same method as in Example 14 or in accordance with the method

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The entitled compound was obtained in the same method as in Example 14 or in accordance with the method or by combining it with an ordinary method but using 4-fluoro-5-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14 and 2-hydroxybenzoic acid dimethylamide in order. The entitled compound was obtained in the same method as in Example 14 or in accordance with the method

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of acetylsalicyloyl chloride (3.4 g, 17 mmol) in 120 mL of THF was added dropwise to 30 mL of 40% aqueous dimethylamine (66 mmol). The mixture was stirred at room temperature for 3 hours and then sodium hydroxide (4 g, 0.1 mmol) was added. The mixture was stirred at room temperature for approximately 60 hours and then poured into 20 mL of water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated. The residue was purified on silica gel by flash chromatography eluting with 6% methanol/methylene chloride to give 2-hydroxy-N,N-dimethylbenzamide (2.4 g, 14.53 mmol), m.p. 145°-152° C. The mixture was stirred at room temperature for approximately 60 hours extracted with ethyl acetate The extract was dried (Na2SO4) concentrated The residue was purified on silica gel by flash chromatography eluting with 6% methanol/methylene chloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of the 2-hydroxy-N,N-dimethylbenzamide (0.68 g) in DMSO (5 ml) was added to a stirred suspension of sodium hydride (163 mg of a 60% dispersion in mineral oil) in DMSO (5 ml) at ambient temperature over 5 minutes with stirring. The mixture was stirred until the evolution of hydrogen ceased and then a solution of 2-chloro-N-[1-(4-chlorophenyl)-1-methylethyl]-acetamide (prepared by reacting α,α-dimethylbenzylamine with chloroacetyl chloride) (1.0 g) in DMSO (5 ml) was added dropwise over 5 minutes with stirring. The mixture was stirred at ambient temperature for 16 hours and then poured into ice water (200 ml) and extracted with ethyl acetate to give a solid which was recrystallised from ethyl acetate/petroleum ether, b.p. 60°-80° C. to give N-(4-chloro-α,α-dimethylbenzyl)-2-(2-dimethylcarbamoyl-phenoxy)acetamide, m.p. 127°-9° C. with stirring The mixture was stirred at ambient temperature for 16 hours extracted with ethyl acetate to give a solid which was recrystallised from ethyl acetate/petroleum ether, b.p. 60°-80° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In an argon atmosphere, a mixture of 6.55 g (39.7 mmol) of 15, 10.9 g (79.3 mmol) of K2CO3, 1.0 g (5.94 mmol) of KI and 80 mL of anhydrous DMF was stirred for 10 min at room temperature. After that 7.52 g (59.5 mmol) of benzyl chloride was added in one portion. The resulting mixture was stirred for 2 hr at 70° C. and then evaporated to dryness. To the residue, 70 mL of water and 30 mL of dichloromethane were added. The organic layer was separated, and the aqueous layer was washed by 2×50 mL of dichloromethane. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. The residue was washed by 50 mL of cold ether and dried in vacuum. Yield 9.71 g (96%) of a white solid. The resulting mixture was stirred for 2 hr at 70° C. evaporated to dryness To the residue, 70 mL of water and 30 mL of dichloromethane were added The organic layer was separated the aqueous layer was washed by 2×50 mL of dichloromethane The combined organic extract was dried over Na2SO4 evaporated to dryness The residue was washed by 50 mL of cold ether dried in vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 156 g (1.13 mol) of salicylic acid and 471 g (3.96 mol) of thionyl chloride was stirred for 4 hr at 50° C.-60° C. Excess thionyl chloride was distilled off under vacuum, and the residue was additionally dried in vacuum. A solution of this product in 300 mL of dichloromethane was added dropwise with vigorous stirring to a mixture of 270 g (3.31 mol) of dimethylamine hydrochloride and 702 g (6.95 mol) of triethylamine in 1200 mL of dichloromethane for 1 hr at 0° C. The resulting mixture was slowly warmed to room temperature, stirred for 1 hr, and then filtered through glass frit. The precipitate was additionally washed with 300 mL of dichloromethane. The combined filtrate was washed by 5% hydrochloric acid, water, dried over K2CO3, and then evaporated to dryness. The residue was washed with 200 mL of diethyl ether to yield 112 g (60%) of white solid. Excess thionyl chloride was distilled off under vacuum the residue was additionally dried in vacuum A solution of this product in 300 mL of dichloromethane was added dropwise stirred for 1 hr filtered through glass frit The precipitate was additionally washed with 300 mL of dichloromethane The combined filtrate was washed by 5% hydrochloric acid, water dried over K2CO3 evaporated to dryness The residue was washed with 200 mL of diethyl ether